Dosed delivery of autonomic modulation therapy

ABSTRACT

An example of a method embodiment may include receiving a user programmable neural stimulation (NS) dose for an intermittent neural stimulation (INS) therapy, and delivering the INS therapy with the user programmable NS dose to an autonomic neural target of a patient. Delivering the INS therapy may include delivering NS bursts, and delivering the NS bursts may include delivering a number of NS pulses per cardiac cycle during a portion of the cardiac cycles and not delivering NS pulses during a remaining portion of the cardiac cycles. The method may further include sensing cardiac events within the cardiac cycles, and controlling delivery of the user programmable NS dose of INS therapy using the sensed cardiac events to time delivery of the number of NS pulses per cardiac cycle to provide the user programmable NS dose. The user programmable NS dose may determine the number of NS pulses per cardiac cycle.

CLAIM OF PRIORITY

This application claims the benefit of priority under 35 U.S.C. §119(e)of U.S. Provisional Patent Application Ser. No. 61/912,274, filed onDec. 5, 2013, which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This document relates generally to medical devices, and moreparticularly, to systems, devices and methods for delivering electricalstimulation.

BACKGROUND

Neural stimulation has been proposed as a therapy for a number ofconditions. Neural stimulation may be delivered to modulate theautonomic system, which may be referred to as an autonomic modulationtherapy (AMT). Examples of AMT include therapies for respiratoryproblems such as sleep disordered breathing, blood pressure control suchas to treat hypertension, cardiac rhythm management, myocardialinfarction and ischemia, heart failure (HF), epilepsy, depression, pain,migraines, eating disorders and obesity, and movement disorders.

AMT may be delivered using intermittently delivered bursts of neuralstimulation pulses. The intensity of this stimulation may be determinedby many stimulation parameters such as pulse width, pulse frequency,ON/OFF timing, and amplitude. What is needed is a more intuitive way ofdosing AMT.

SUMMARY

Various embodiments provided herein may provide a simpler, intuitive wayfor dosing AMT by delivering AMT as a dose per cardiac cycle. An exampleof a method embodiment may include receiving a user programmable neuralstimulation (NS) dose for an intermittent neural stimulation (INS)therapy, and delivering the INS therapy with the user programmable NSdose to an autonomic neural target of a patient. Delivering the INStherapy may include delivering NS bursts, and delivering the NS burstsmay include delivering a number of NS pulses per cardiac cycle during aportion of the cardiac cycles and not delivering NS pulses during aremaining portion of the cardiac cycles. The method may further includesensing cardiac events within the cardiac cycles, and controllingdelivery of the user programmable NS dose of INS therapy using thesensed cardiac events to time delivery of the number of NS pulses percardiac cycle to provide the user programmable NS dose. The userprogrammable NS dose may determine the number of NS pulses per cardiaccycle.

An example of a method embodiment for programming a neural stimulator todeliver intermittent neural stimulation (INS) to an autonomic neuraltarget of a patient, where the INS therapy includes neural stimulation(NS) ON times alternating with NS OFF times, may include programming avalue in units of NS pulses per cardiac cycle for an programmable NSdose parameter for the INS therapy. The INS therapy may include an NSburst of NS pulses during a portion of the cardiac cycle correspondingto one of the NS ON times and no NS pulses during a remaining portion ofthe cardiac cycle corresponding to one of the NS OFF times. The numberof pulses in the NS burst may be the number of NS pulses per cardiaccycle. Some embodiments may further include programming the pulseamplitude for the burst of pulses.

An example of a system may include a cardiac cycle monitor, a neuralstimulator, a memory and a communication system. The cardiac cyclemonitor may be configured to monitor cardiac events within cardiaccycles. The neural stimulator may be configured to deliver neuralstimulation (NS) to the autonomic neural target. The memory may beconfigured to store a programmable NS dose parameter for an intermittentneural stimulation (INS) therapy. The programmable NS dose parameter mayinclude a value for a number of NS pulses per cardiac cycle. Thecommunication system may be configured to receive programminginstructions for the NS dose parameter including the value for thenumber of NS pulses per cardiac cycle, and store the value for thenumber of NS pulses per cardiac cycle in the memory. The controller maybe configured to control the neural stimulator to deliver the INStherapy to the autonomic neural target. The controller, the memory, theneural stimulator and the cardiac cycle monitor may be configured tocooperate to implement a process to deliver the INS therapy where theprocess includes sensing a cardiac event within a cardiac cycle; anddelivering NS bursts of NS pulses. Delivering NS bursts may includetiming delivery of the NS bursts using the sensed cardiac events withinthe cardiac cycles. The number of NS pulses per cardiac cycle may bedelivered during a first portion of a cardiac cycle, and the remainingportion of the cardiac cycle may be without NS pulses.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the disclosure will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof, each of which are not tobe taken in a limiting sense. The scope of the present disclosure isdefined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIG. 1 illustrates, by way of example, an embodiment of a system thatprovides neural stimulation that is synchronized to the cardiac cycleand that uses using an NS dose of pulses per cardiac cycle.

FIG. 2 illustrates an example of a system which may be a more specificembodiment of the system in FIG. 1.

FIG. 3 illustrates an example of a dose control module, which may bespecific example of a dose control module in FIG. 1 or FIG. 2.

FIG. 4 illustrates, by way of example, an NS burst of NS pulses.

FIG. 5 illustrates, by way of example, a representation of intermittentneural stimulation (INS).

FIG. 6 illustrates, by way of example, a representation of an additionallayer of ON/OFF timing for the neural stimulation.

FIG. 7 illustrates, by way of example, a general relationship between anelectrocardiogram (ECG), a pressure waveform within a blood vessel (e.g.pulmonary artery) and the refractory period of the heart during systolicand diastolic portions of a cardiac cycle.

FIG. 8 illustrates an example of a NS burst of NS pulses deliveredduring an NS window that generally corresponds to at least a portion ofthe refractory period of the heart as illustrated by the ECG signal.

FIG. 9 illustrates, by way of example, some embodiments of NS bursttiming.

FIG. 10 illustrates, by way of example, some embodiments of NS bursttiming with respect to the refractory period.

FIG. 11 illustrates, by way of example, some NS burst timing withrespect to cardiac cycles.

FIGS. 12-14 illustrate, by way of example, various embodiments fordelivering a NS burst of pulses during a cardiac cycle.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. For example, neural stimulation as used hereinmay refer to stimulation that elicits nerve traffic in a neural target.However, a neural target may be stimulated with appropriate stimulationparameters to reduce or block nerve traffic at the neural target.References to “an”, “one”, or “various” embodiments in this disclosureare not necessarily to the same embodiment, and such referencescontemplate more than one embodiment. The following detailed descriptionis, therefore, not to be taken in a limiting sense, and the scope isdefined only by the appended claims, along with the full scope of legalequivalents to which such claims are entitled.

Neural stimulation may be delivered to stimulate the autonomic nervoussystem (ANS). For example, the neural stimulation may be directed tostimulating a vagus nerve in the neck (e.g. cervical vagus nerve) or tostimulating various nerves that branch from the vagus nerve trunk. Theneural stimulation may be directed to other autonomic nervous systemtargets. Examples of other autonomic neural stimulation targets includebut are not limited to baroreceptor regions such as may be found in thecarotid sinus region or in the pulmonary artery, chemoreceptor regions,the glossopharyngeal nerve, the carotid sinus nerve, and spinal nerves.The ANS regulates “involuntary” organs. Examples of involuntary organsinclude respiratory and digestive organs, and also include blood vesselsand the heart. Often, the ANS functions in an involuntary, reflexivemanner to regulate glands, to regulate muscles in the skin, eye,stomach, intestines and bladder, and to regulate cardiac muscle and themuscles around blood vessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.Afferent neurons convey impulses towards the central nervous system(CNS), and efferent neurons convey impulses away from the CNS.

Stimulating the sympathetic and parasympathetic nervous systems cancause heart rate, blood pressure and other physiological responses. Forexample, stimulating the sympathetic nervous system may dilate thepupil, reduce saliva and mucus production, relax the bronchial muscle,reduce the successive waves of involuntary contraction (peristalsis) ofthe stomach and the motility of the stomach, increase the conversion ofglycogen to glucose by the liver, decrease urine secretion by thekidneys, and relax the wall and closes the sphincter of the bladder.Stimulating the parasympathetic nervous system (inhibiting thesympathetic nervous system) may constrict the pupil, increase saliva andmucus production, contract the bronchial muscle, increase secretions andmotility in the stomach and large intestine, increase digestion in thesmall intestine, increase urine secretion, and contract the wall andrelax the sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other. A therapy which intentionallyaffects the parasympathetic activity and/or sympathetic activity withinthe ANS may be referred to as an Autonomic Modulation Therapy (AMT). Aneural stimulation therapy delivered to an autonomic neural target is anexample of an AMT. The vagus nerve is an example of an autonomic neuraltarget. For example, the cervical vagus nerve may be stimulated to treatconditions such as, by way of example and not limitation, hypertension,heart failure, arrhythmias and pain. Other examples of conditions thatmay be treatable using vagus nerve stimulation include, but are notlimited to, migraines, eating disorders, obesity, inflammatory diseases,and movement disorders. Other autonomic neural targets include, but arenot limited to, baroreceptor regions, chemoreceptor regions, cardiac fatpads, various branches of the vagus nerve, the carotid sinus nerve, andthe glossopharyngeal nerve.

A reduction in parasympathetic nerve activity contributes to thedevelopment and progression of a variety of cardiovascular diseases.Some embodiments of the present subject matter can be used toprophylactically or therapeutically treat various cardiovasculardiseases by modulating autonomic tone. Neural stimulation to treatcardiovascular diseases may be referred to as neurocardiac therapy(NCT). Vagal stimulation used to treat cardiovascular diseases may bereferred to as either vagal stimulation therapy (VST) or NCT. However,VST may be delivered for non-cardiovascular diseases, and NCT may bedelivered by stimulating a nerve other than the vagal nerve. Examples ofcardiovascular diseases or conditions that may be treated using AMTinclude hypertension, HF, and cardiac remodeling. These conditions arebriefly described below.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to HF. Hypertension generally relates tohigh blood pressure, such as a transitory or sustained elevation ofsystemic arterial blood pressure to a level that is likely to inducecardiovascular damage or other adverse consequences. Hypertension hasbeen defined as a systolic blood pressure above 140 mm Hg or a diastolicblood pressure above 90 mm Hg. Consequences of uncontrolled hypertensioninclude, but are not limited to, retinal vascular disease and stroke,left ventricular hypertrophy and failure, myocardial infarction,dissecting aneurysm, and renovascular disease. A large segment of thegeneral population, as well as a large segment of patients implantedwith pacemakers or defibrillators, suffer from hypertension. The longterm mortality as well as the quality of life can be improved for thispopulation if blood pressure and hypertension can be reduced. Manypatients who suffer from hypertension do not respond to treatment, suchas treatments related to lifestyle changes and hypertension drugs.

HF refers to a clinical syndrome in which cardiac function causes abelow normal cardiac output that can fall below a level adequate to meetthe metabolic demand of peripheral tissues. HF may present itself ascongestive heart failure (CHF) due to the accompanying venous andpulmonary congestion. HF can be due to a variety of etiologies such asischemic heart disease. HF patients have impaired autonomic balance,which is associated with LV dysfunction and increased mortality.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)account for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

It has been proposed to deliver bursts of neural stimulation pulsessynchronized to a cardiac cycle. One example of such a system isprovided in U.S. application Ser. No. 61/912/315, filed on the same dateas the present application, and entitled “Intuited Delivery of AutonomicModulation Therapy” , which application is incorporated by referenceherein in its entirety. Thus, for example, various embodiments describedherein may deliver estimate cardiac timing.

Various embodiments provided herein use a dose per cardiac cycle todeliver AMT. For example, the dose per cardiac cycle may simply becontrolled using the number of pulses to be delivered within a cardiaccycle. A benefit of such an approach is more intuitive programming thatcan reduce the number of programmed parameters. For example if thenumber of pulses per cardiac cycle is preprogrammed, the clinician mayonly need to program amplitude to control the intensity of AMT. In someembodiments the clinician is able to control the number of pulsesdelivered per cardiac cycle. In some embodiments, the clinician may beable to program both the number of pulses delivered per cardiac cycleand amplitude of the pulses.

Additionally, lower frequencies may be more tolerable for patients atrest, and patients are mostly at rest. Further, it is believed thatpatients may better tolerate AMT delivered with an increased frequencywhen active. As an exaggerated systolic blood pressure response toexercise may be associated with increased left ventricular mass, it maybe desirable to increase VNS or other AMT that elicits a parasympatheticresponse to counter to blood pressure response.

Some embodiments may be configured to mimic healthy nerve activityresponse to cardiac activity. For example, “n” pulses may be deliveredwithin natural cardiac tissue refractory period. Some embodiments mayadjust the stimulation to account for changes in the cardiac cycle asrate changes. For example, the refractory period decreases as theintrinsic or paced heart rate increases. Some system embodimentsautomatically adjust the frequency of AMT burst delivery to distributethe pulses during the tissue refractory to maintain same number ofpulses delivered within tissue refractory and/or device sense refractorywindows.

The intuitive programming may use several pre-set program modes. Forexample, a nominal mode such as but not limited to two pulses per cycleand a high output mode such as but not limited to four pulses per cyclemay be used. A dynamic mode may be used to switch between two modes oramong more than two modes. For example, two pulses per cycle may bedelivered during a resting state and four pulses per cycle may bedelivered during an active state. The modes may switch based onactivity, rate, and/or minute ventilation (MV) sensing, by way ofexample and not limitation.

The number of pulses per cardiac cycle may increase as rate goes down.Furthermore, there may be no change in the pulse frequency of the burstof pulses. As the rate goes down, the window of time (e.g. refractoryperiod) for delivering pulses may increase.

The number of pulses per cardiac cycle may decrease as rate goes down.There is less intrinsic sympathetic activity at lower rates. Thus, atherapy that mimics or follows the intrinsic sympathetic activity maydeliver fewer pulses per cardiac cycle for lower cardiac rates.Furthermore, there may be no change in pulse frequency with the fewerpulses. The reduced number of pulses at resting rates may be moretolerable. Additionally, as a patient is usually at a resting rate, thereduced number of delivered pulses may increase the life of abattery-powered neural stimulator.

A dynamic system may adjust both the number of pulses and the pulsefrequency. For example, a dynamic system may increase the number ofpulses per cycle with an increasing rate, and increase the frequencybetween pulses with increasing rate to stay within shrinking refractorywindow.

A dynamic system may change one or more neural stimulation parametersbased on heart rate, or activity or a blended sensor that has heart rateand activity inputs. These neural stimulation parameters may include oneor more of a pulse width, an amplitude, a product of pulse width andamplitude (e.g. product=pulse width*amplitude), and pulse frequency.

Some embodiments may program the duty cycle based on cardiac cycles. Byway of example and not limitation, the system may be programmed toprovide a stimulation ON portion of the duty cycle for 10 cardiaccycles, and to provide a stimulation OFF portion of the duty cycle for50 cardiac cycles. This programmed duty cycle may be adjusted based on adetected heart rate. For example, the number of cardiac cycles may bedecreased as rate increases. For example, the decrease may be used tomaintain the average amount of charge delivered over a period of time(e.g. minute). By way of example and not limitation, if the system isprogrammed with a stimulation ON portion of the duty cycle of 10 cardiaccycles and a stimulation OFF portion of the duty cycle of 50 cardiaccycles at a heart rate of 60 beats per minute, the system may beprogrammed to respond to a detected heart rate of 120 beats per minuteby changing the stimulation ON portion of the duty cycle to 5 cardiaccycles and the stimulation OFF portion of the duty cycle to 55 cardiaccycles. Thus, assuming the pulse width does not change, the energydelivered over one minute remains the same whether the heart rate is 60beats per minute (e.g. 10 pulses delivered during the first 10 cardiaccycles from about time 0 seconds to about 10 seconds) or 120 beats perminutes (e.g. 5 pulses delivered during the first five cardiac cyclesfrom about 0 seconds to about 2.5 seconds and 5 pulses delivered duringthe 60^(th) to 65^(th) cardiac cycles from about 30 seconds to about32.5 seconds).

The dose of cardiac pulses may be delivered at a specific time, ortimes, within the cardiac cycle. Thus, various embodiments may determinea cardiac event and use the cardiac event to time the delivery of the NSburst of pulses. A cardiac event may be determined by ECG, monitoredblood pressure wave (plethysmography), heart sounds, carotid sounds,cardiac pace detection (nearly 100% of cardiac cycles for CRT), infotransferred from other device (external, ICD, pressure monitor, etc.).These examples are provided as non-limiting examples. A cardiac “event”may be a “time-out” from the last detected cardiac event, similar to alower rate limit (LRL) for a cardiac rhythm management (CRM) device suchas a pacemaker). Some detected cardiac events, such as a prematureventricular contraction (PVC), antitachycardia pacing (ATP), or a LRLmay trigger a specific does with a frequency determined by cardiac rate.A current cardiac rate may be determined on a cycle by cycle basis (i.e.pacemaker-like) or based on an average of preceding cycles. For example,the cardiac rate may be based on last four cardiac cycles by way ofexample and not limitation. The average may be based on other number ofcardiac cycles.

U.S. Pat. No. 7,542,800, entitled “Method and Apparatus forSynchronizing Neural Stimulation to Cardiac Cycles”, assigned to CardiacPacemakers, Inc.” discusses and example for synchronizing neuralstimulation to cardiac cycle. U.S. Pat. No. 7,542,800 is incorporated byreference in its entirety. The present subject matter can be implementedwithin such a system, as it controls the NS dose delivered per cardiaccycle.

FIG. 1 illustrates, by way of example, an embodiment of a system thatprovides neural stimulation that is synchronized to the cardiac cycleand that uses an NS dose of pulses per cardiac cycle. The illustratedsystem 100 may include a first system 101, such as an implantabledevice, and a second system 102, such as an external device, used forprogramming the first device. The illustrated first system 101 mayinclude a cardiac cycle-synchronized neural stimulation circuit 103, NSelectrodes 104 for use in delivering neural stimulation, and a referencesignal sensor 105 for use in detecting a reference within a cardiaccycle. Detection of the reference allows the circuit 103 to synchronizedelivering of a burst of NS pulses within the cardiac cycle. The firstsystem 101 may further include an activity sensor or sensors 106 andanother physiological sensor or sensors 107 which may be used to providefeedback for a NS therapy delivered by the first system 101 or to senseand record diagnostic data for evaluation by a user of the system.

The reference signal sensor 105 senses a reference signal indicative ofcardiac cycles. The reference signal sensor 105 may be an implantablereference signal sensor. The timing reference event is a recurringfeature of the cardiac cycle that is chosen to be a timing reference towhich the neural stimulation is synchronized. The reference signalsensor 105 may be configured for extracardiac and extravascularplacement, i.e., placement external to the heart and blood vessels.Examples of reference signal sensors may include a set of electrodes forsensing a subcutaneous ECG signal, an acoustic sensor for sensing anacoustic signal indicative of heart sounds, and a hemodynamic sensor forsensing a hemodynamic signal indicative of hemodynamic performance. Thefirst system 101 may have an implantable housing that contains both areference signal sensor 105 and cardiac cycle-synchronized neuralstimulation circuit 103. In an embodiment, reference signal sensor 105is incorporated onto the implantable housing. In an embodiment, thereference signal sensor 105 is electrically connected to the firstsystem 101 through one or more leads. In an embodiment, the referencesignal sensor 105 may be communicatively coupled to first device orsystem 101 via an intra-body telemetry link.

The cardiac cycle-synchronized neural stimulation circuit 103 mayinclude a stimulation output circuit 108, a reference event detectioncircuit 109, and a stimulation control circuit 110. The reference eventdetection circuit 109 receives the reference signal from referencesignal sensor 105 and detects the timing reference event from thereference signal. The stimulation control circuit 110 controls thedelivery of the neural stimulation pulses and includes a synchronizationcircuit 111. The synchronization circuit 111 may be configured toreceive signal indicative of the detection of each timing referenceevent and synchronizes the delivery of the neural stimulation pulses tothe detected timing reference event. The stimulation output circuit 108may be configured to deliver neural stimulation pulses upon receiving apulse delivery signal from the stimulation control circuit 110. Thefirst system 101 may further include an activity discriminator 112 todetermine an activity level based on the output from the activitysensor(s) 106. The stimulation control circuit 110 may include a dosecontrol module 113 configured to control the NS dose by controlling theburst of NS pulses delivered per cardiac cycle. The stimulation controlcircuit 113 may use activity and/or other sensed physiologicalparameters to control the dose delivered per cardiac cycle.

The cardiac cycle-synchronized neural stimulation circuit 103 mayinclude a memory 114 which may contained preprogrammed oruser-programmable NS doses 115 for delivering one or more bursts of NSpulses within a cardiac cycle, and may further include communicationcircuitry 116 for use in communicating with the second system 102. Thesecond system 102 has communication circuitry 117 for use incommunication with the communication circuitry 116 of the first deviceor system 101. The second system 102 further includes a dose programminginterface 118 for use by a user to program the dose(s) into the memory114. The dose may be delivered as pulses per cardiac cycle. In someembodiments a desired number of pulses per cardiac cycle may beprogrammed as a desired dose. In some embodiments a maximum number ofpulses per cycle may be programmed as a maximum dose where the system isconfigured to adjust the dose to allowable dosages less than the maximumdose. Furthermore, according to some embodiments a user may use thesecond device or system 102 to program a desired amplitude of the NSpulses delivered within an NS dose. Thus, the amplitude of the NS pulsesmay be a programmable parameter regardless of whether the number ofpulses per cardiac cycle is a user-programmable value or a preprogrammedvalue. The second system 102 may also include a display, and may beconfigured to provide an indication to the physician how muchstimulation is being delivered over a period of time. This indicationmay be referred to as a dose meter. The dose meter informs the physicianhow much stimulation (e.g. number of pulses, or total charge delivered)is or will be delivered. Various combinations of pulse parameters can bedisplayed to provide a calculated or estimated dose. For example, aproduct of amplitude and pulse number may be used to provide an estimateof the dose over the period of time. By way of example but notlimitation, the period of time may be an hour or a day. Furthermore, thedose meter may provide current dose information that reflects the dosedelivered using the currently-programmed stimulation parameters, and mayalso provide dose information for a proposed stimulation parameterswhich allows the physician to confirm the dose information beforeprogramming those parameters into the memory 114 of the first system101.

FIG. 2 illustrates an example of a system which may be a more specificembodiment of the system in FIG. 1. The system 201 includes a cardiaccycle-synchronized neural stimulation circuit 203, which is a specificembodiment of the cardiac cycle-synchronized neural stimulation circuit103 in FIG. 1. The cardiac cycle-synchronized neural stimulation circuit203 includes a stimulation output circuit 208, a reference eventdetection circuit 209, and a stimulation control circuit 210.

The reference event detection circuit 209 may be a specific embodimentof the reference event detection 109 and includes a signal processor 219and an event detector 220. The signal processor 219 receives thereference signal sensed by the reference signal sensor 205 and processesthe reference signal in preparation for the detection of the timingreference events by event detector 220. The event detector 220 mayinclude a comparator having an input to receive the processed referencesignal, another input to receive a detection threshold, and an outputproducing a detection signal indicating a detection of the timingreference signal. In an embodiment, the signal processor 219 processesthe reference signal to provide for extraction of the timing referenceevent based on a single cardiac cycle. In an embodiment, the signalprocessor 219 includes a filter having a pass-band corresponding to afrequency range of the timing reference event to prevent unwantedactivities in the reference signal from being detected by event detector220. In an embodiment, the signal processor 219 includes a blankingperiod generator to generate a blanking period that blanks the unwantedactivities in the reference signal. This approach is applied when anapproximate timing relationship between the timing reference event andthe unwanted activities, or an approximate timing relationship betweenanother detectable event and the unwanted activities, is predictable. Inan embodiment, the blanking period generator generates a blanking periodthat blanks cardiac pacing artifacts in the reference signal, i.e.,unwanted activities caused by delivery of cardiac pacing pulses. In anembodiment, the signal processor 219 includes a timing intervalgenerator to generate a timing interval between an intermediate eventand the timing reference event. This approach is applied when theintermediate event is more easily detectable than the timing referenceevent and when an approximate timing relationship between theintermediate event and the timing reference event is predictable. In anembodiment, the signal processor 219 processes the reference signal toprovide for extraction of the timing reference event based on aplurality of cardiac cycles. In one specific embodiment, the signalprocessor 219 includes a signal averaging circuit that averages thereference signal over a predetermined number of cardiac cycles beforethe detection of the timing reference event by event detector 220.

The stimulation control circuit 210 may be a more specific embodiment ofstimulation control circuit 110 and includes a synchronization circuit211, and a dose control 213. The illustrated dose control 213 mayinclude an offset interval generator 221 and a pulse delivery controller222. The synchronization circuit 211 may include one or both of acontinuous synchronization module 223 and a periodic synchronizationmodule 224. The continuous synchronization module 223 synchronizes thedelivery of the neural stimulation pulses to the timing reference eventof consecutive cardiac cycles. A periodic synchronization module 224synchronizes the delivery of the neural stimulation pulses to the timingreference event of selected cardiac cycles on a periodic basis. Anoffset interval generator 221 produces an offset interval starting withthe detected timing reference event. A pulse delivery controller 222sends the pulse delivery signal to start a delivery of a burst of aplurality of neural stimulation pulses when the offset interval expires.For example, the pulse delivery controller 222 may send the pulsedelivery signal after the detection of the timing reference event foreach of consecutive cardiac cycles. In an example, the pulse deliverycontroller 222 sends the pulse delivery signal after the detection ofthe timing reference event for selected cardiac cycles according to apredetermined pattern or programmed schedule, such as on a periodicbasis. The illustrated system 201 may also include NS electrodes 104 foruse in stimulating a neural target, communication circuitry 216 andmemory 214 with programmed dose(s) 215 as generally illustrated anddiscussed with respect to FIG. 1. The illustrated system may alsoinclude physiological sensor(s) 207, activity sensor(s) 206, and anactivity discriminator 212 as generally illustrated and discussed withrespect to FIG. 1.

FIG. 3 illustrates an example of a dose control module 313, which may bespecific example of a dose control module 113 in FIG. 1 or a dosecontrol module 213 in FIG. 2. The illustrated dose control module 313uses the programmed dose 315 to control the number of pulses per cardiaccycle. The dose control module 313 may also include a dose adjustmentmodule 325 for adjusting the programmed dose based on received input forthe dose adjustment 326. For example, the dose control module 313 may beconfigured to change the pulses frequency 327 of the NS pulses deliveredduring a cardiac cycle, or the duration 328 of the burst of pulsesdelivered during a cardiac cycle, the amplitude 329 of the NS pulsesdelivered within the burst, or change the number of pulses per cardiaccycle 330. The dose adjustment module 325 may further be configured tocontrol the allowable doses 331 that can be delivered during a cardiaccycle. For example, the number of pulses that may be delivered may bepreprogrammed doses, or may be user-programmable doses. The number ofpulses that may be delivered in a given cardiac cycle may be limited bya maximum number and/or limited by a minimum number. Further, limits(minimum and/or maximum) may be placed on the pulse frequency, the burstduration, and/or the amplitude. These limits may be programmed limitsand/or may be derived from the programmed doses. For example, the systemmay be configured to determine the allowable range of doses based on aprogrammed maximum dose of NS pulses per cardiac cycle. Some systemembodiments may use heart rate 332, and/or activity 333, and/or anotherphysiological parameter 334 as an input to control the dose adjustment.In some embodiments, the system records the heart rate 332, and/oractivity 333, and/or another physiological parameter 334 forcommunication to the second system to enable a user to review thesemeasurements and adjust programming.

FIG. 4 illustrates an NS burst 435 of NS pulses 436. The NS burst 435has a number of NS pulses 436, which can be delivered during a cardiaccycle and can define a NS dose of NS pulses per cardiac cycle. The NSpulses delivered within the burst may have a consistent pulse width anda repeated pulse interval. Those of ordinary skill in the art willappreciate that the pulse interval may be referred to as a pulsefrequency as a pulse occurs after a period of time (e.g. pulseperiod=1/pulse frequency). The illustrated pulses also have anamplitude.

The intensity of neural stimulation is affected by the amount of chargedelivered to the target, as well as the density of the charge deliveredto the target during the period of time. This amount of charge dependson the amplitude, the pulses width, and the pulse frequency of thepulses affect the amount of delivered charge, and thus can affect thedose. This can become complicated to program and control, particularlyfor intermittent neural stimulation that may deliver NS bursts of NSpulses during an ON period of time and then deliver no neuralstimulation during an OFF period of time. According to variousembodiments, the dosing of the neural stimulation is characterized usingthe number of pulses per cardiac cycle. The amplitude of these NS pulsesmay be adjusted to further control the NS dose of the therapy.

FIG. 5 illustrates a representation of intermittent neural stimulation(INS). The figure diagrammatically shows the time-course of a neuralstimulation that alternates between intervals of stimulation being ON,when one stimulation pulse or a set of grouped stimulation pulses (i.e.,a burst 535) is delivered, and intervals of stimulation being OFF, whenno stimulation pulses are delivered. Thus, for example, some embodimentsdeliver a plurality of monophasic or biphasic pulses within a neuralstimulation burst 435 illustrated in FIG. 4. The duration of thestimulation ON interval is sometimes referred to as the stimulationduration or burst duration 537. The burst duration also affects the doseof the neural stimulation therapy. The start of a stimulation ONinterval is a temporal reference point NS Event 538. The NS Event may bea sensed event or derived from a sensed event or a programmed time. Thetime interval between successive NS Events is the INS Interval 539,which is sometimes referred to as the stimulation period or burstperiod. The burst period or the number of neural stimulation events thatoccur over a time period also affect the dose of the neural stimulation.For an application of neural stimulation to be intermittent, thestimulation duration 537 is less than the stimulation period (i.e., INSInterval 539). The duration of the OFF intervals of INS are determinedby the durations of the ON interval and the INS Interval. The durationof the ON interval relative to the INS Interval (e.g., expressed as aratio) is sometimes referred to as the duty cycle of the INS. Thepresent subject matter may deliver a burst of NS pulses within a cardiaccycle, and may further deliver the burst of NS pulses timed to a desiredtime within the cardiac cycle. One or more bursts of NS pulses may bedelivered during a NS ON time 540.

FIG. 6 illustrates a representation of an additional layer of ON/OFFtiming for the neural stimulation. By way of example and not limitation,the INS illustrated in FIG. 5 as being delivered during NS ON time 540may be delivered during NS ON times 640 over one or more cardiac cycles.These NS ON times 640 are separated by NS OFF times 641 over one or morecardiac cycles without NS pulses.

FIG. 7 illustrates a general relationship between an electrocardiogram(ECG) 742, a pressure waveform 743 within a blood vessel (e.g. pulmonaryartery) and the refractory period 744 of the heart during systolic anddiastolic portions of a cardiac cycle. Systole is the portion of thecardiac cycle when the heart contracts to force blood through thecirculatory system. Diastole is the portion of the cardiac cycle whenthe heart expands to fill with blood. Blood pressure increases duringsystole.

The cardiac refractory period 744 is separated into an absoluterefractory period (ARP) and a relative refractory period (RRP). Duringthe absolute refractory period, a new action potential cannot beelicited during the absolute refractory period but may be elicited witha greater than normal stimulus during the relative refractory period.The refractory period generally begins with the QRS waveform 745 andextends through the T wave 746. Various detectable cardiac events withinthe cardiac cycle may be used to tie the delivery of NS bursts. Examplesof such detectable cardiac events include but are not limited to the Pwave 747, Q wave 748, R wave 749, S wave 750 or T wave 746, or differentdetectable heart sounds for example. Some embodiments may time thedelivery of the NS burst of NS pulses to occur during at least a portionof the refractory period (i.e. during at least a portion of the absoluteand/or relative refractory periods). For example, baroreceptors sensepressure and elicit a baroreflex response. Neural stimulation to elicita baroreflex response may be timed to occur during the refractory periodto augment the natural baroreflex response. FIG. 8 illustrates anexample of a NS burst of NS pulses 836 delivered during an NS window 851that generally corresponds to at least a portion of the refractoryperiod of the heart as illustrated by the ECG signal 842. In someembodiments, the delivery of the NS burst of NS pulses may be timed tooccur during diastole to reduce the pulsation of the naturally-elicitedbaroreflex response.

FIG. 9 illustrates, by way of example and not limitation, someembodiments of NS burst timing. In a first example, the NS burst isdelivered during a window of time beginning with the detected cardiacevent. The initiation of the NS burst may begin with the detectedcardiac cycle. In the illustrated examples, the cardiac eventcorresponds with the R wave 949 in the ECG signal 943. The duration ofthe NS burst may be a programmable parameter. In a second example, theNS burst is initiated an offset period of time after detection of thecardiac event. In a third example, the NS burst is initiated at offsetperiod of time before the cardiac event.

FIG. 10 illustrates some NS burst timing with respect to the refractoryperiod 1044, by way of examples and not limitation. In a first example1055, the NS burst window, within which the burst of NS pulses may bedelivered, generally begins as the refractory period begins and endswhen the refractory period ends. In a second example 1056, the NS burstwindow, within which the burst of NS pulses may be delivered, generallybegins as the absolute refractory period beings and ends as the absoluterefractory period ends. In a third example 1057, the NS burst window,within which the burst of NS pulses may be delivered, generally beginsat the beginning of the relative refractory period and ends as therelative refractory period ends. In a fourth example 1058, the NS burstwindow, within which the burst of NS pulses may be delivered, may beginbefore the refractory period begins and/or may end after the refractoryperiod ends. In a fifth example 1059, the NS burst window, within whichthe burst of NS pulses may be delivered, generally begins and endswithin the refractory period. In the sixth example 1060, the NS burstwindow, within which the burst of NS pulses may be delivered, generallybegins and ends within the absolute refractory period. In a seventhexample 1061, more than one NS burst window may be provided within therefractory period.

FIG. 11 illustrates some NS burst timing with respect to cardiac cycles.In a first example 1162, a NS burst of NS pulses is delivered duringevery cardiac cycle. In a second example 1163, a NS burst of NS pulsesis delivered only is some of the cardiac cycles, and is not delivered inother cycle. For example, the NS burst may be delivered every othercardiac cycle. The determination of which cardiac cycles within which todeliver a NS burst may be based on a timer. For example, afterexpiration of a timer a NS burst may be delivered during each of thenext one or more cardiac cycles; or after expiration of a timer apattern of cardiac cycles a NS burst may be delivered for a pattern ofcardiac cycles (e.g. every N cardiac cycles). The determination of whichcardiac cycles within which to deliver a NS burst may be based on asensed physiological parameter.

FIGS. 12-14 illustrate various embodiments for delivering a NS burst ofpulses during a cardiac cycle. These processes may be implemented, forexample, using any of the systems illustrated in FIGS. 1-3. Theprocesses may be implemented using hardware, software and/or firmware.

In FIG. 12, an NS dose may be programmed into the system. For example,the programmed dose may be stored in memory 114 or 214. The dose may beprogrammed as a number of pulses per cardiac cycle, or may be programmedas a combination of the number of pulses per cycle and the amplitude ofthe pulses. The current cardiac rate may be measured a variety of ways.By way of example and not limitation, a heart rate sensor, an ECGsensor, a heart sound sensor, a blood pressure sensor, or a blood flowsensor may be used to determine a cardiac rate. The current cardiac rateis used to determine or update the timing between NS pulses (“NS pulsefrequency”). Upon detection of a cardiac event, the NS burst isdelivered using the updated NS pulse frequency.

In FIG. 13, a maximum dose is programmed into the system. The dose maybe programmed as a number of pulses per cardiac cycle, or may beprogrammed as a combination of the number of pulses per cycle and theamplitude of the pulses. The current cardiac rate may be measured andused to determine or update the timing between NS pulses (“NS pulsefrequency”) and/or may be used to modify the number of pulses in theburst without exceeding the programmed maximum dose. Upon detection of acardiac event, the NS burst is delivered using the updated NS pulsefrequency.

In FIG. 14, a maximum dose is programmed into the system. The dose maybe programmed as a number of pulses per cardiac cycle, or may beprogrammed as a combination of the number of doses and number of pulses.The current cardiac rate may be measured and used to determine or updatethe timing between NS pulses (“NS pulse frequency”) and/or may be usedto modify the number of pulses in the burst without exceeding theprogrammed maximum dose. Furthermore, the patient's activity may bemonitored, and this monitored activity may be used as a factor indetermining or updating timing between NS pulses (“NS pulse frequency”)and/or may be used to modify the number of pulses in the burst. Thepatient's activity may be monitored using sensor(s) such as, but notlimited to, accelerometer-based sensors, heart rate sensors, bloodpressure sensors, and/or respiration sensors. A discriminator candetermine the patient's activity level based on the output(s) from suchsensor(s). Upon detection of a cardiac event, the NS burst is deliveredusing the updated NS pulse frequency.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of ordinaryskills in the art upon reading and understanding the above description.The scope of the disclosure should, therefore, be determined withreferences to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

What is claimed is:
 1. A method, comprising: receiving a userprogrammable neural stimulation (NS) dose for an intermittent neuralstimulation (INS) therapy; delivering the INS therapy with the userprogrammable NS dose to an autonomic neural target of a patient, whereindelivering the INS therapy includes delivering NS bursts, whereindelivering the NS bursts includes delivering a number of neuralstimulation (NS) pulses per cardiac cycle during a portion of thecardiac cycles and not delivering NS pulses during a remaining portionof the cardiac cycles, the user programmable NS dose determining thenumber of NS pulses per cardiac cycle; sensing cardiac events within thecardiac cycles; controlling delivery of the user programmable NS dose ofINS therapy using the sensed cardiac events to time delivery of thenumber of NS pulses per cardiac cycle to provide the user programmableNS dose; and displaying a dose meter on a display to provide anindicator of a dose over a period of time including a total chargedelivered over the period of time, and the indicator of the doseprovided on the displayed dose meter is for a current user programmableNS dose, or for a user proposed NS dose, or for both the current userprogrammable NS dose and the user proposed NS dose.
 2. The method ofclaim 1, wherein the number of NS pulses per cardiac cycle are deliveredduring an NS ON window of time, and controlling delivery of the userprogrammable NS dose of INS therapy using the sensed cardiac eventsincludes controlling the delivery of the number of NS pulses per cardiaccycle to occur within a refractory period of the cardiac cycle.
 3. Themethod of claim 1, wherein: the number of NS pulses per cardiac cycleare delivered during an NS ON window of time where the NS ON window oftime lengthens as the cardiac cycle duration increases and decreases asthe cardiac cycle duration decreases; and controlling delivery of theuser programmable NS dose of INS therapy using the sensed cardiac eventsto time delivering of the number of NS pulses per cardiac cycle includeschanging a pulse frequency to distribute the NS pulses across the NS ONwindow of time, wherein the pulse frequency increases as the NS windowof time decreases and the pulse frequency decreases as the NS window oftime increases.
 4. The method of claim 1, wherein the number of NSpulses per cardiac cycle to be delivered during a portion of the cardiaccycles includes pre-set doses, the pre-set doses including a normal doseof a first number of pulses per cycle and a higher dose of a secondnumber of pulses per cycle, the second number being greater than thefirst number.
 5. The method of claim 1, wherein the number of NS pulsesper cardiac cycle to be delivered during a portion of the cardiac cyclesincludes pre-set doses that includes a dynamic dose to deliver a firstnumber of pulses per cycle during an active state and a second number ofpulses per cycle during a resting state, the method further includingsensing if a patient is in the resting state or the active state, anddelivering the dynamic dose based on whether the patient is in theresting state or the active state.
 6. The method of claim 1, wherein themethod further includes: sensing a physiological parameter wherein thesensed physiological parameter includes sensed heart rate, sensedactivity or sensed minute ventilation, and adjusting, based on thesensed physiological parameter, the number of NS pulses per cardiaccycle to be delivered during the portion of the cardiac cycles.
 7. Themethod of claim 6, wherein the sensed physiological parameter isindicative of heart rate changes, and adjusting includes increasing thenumber of NS pulses per cycle from the programmable number when thesensed physiological parameter indicates a decreased heart rate.
 8. Themethod of claim 6, wherein the sensed physiological parameter isindicative of heart rate changes, and adjusting includes increasing thenumber of NS pulses per cycle from the programmable number when thesensed physiological parameter indicates an increased heart rate.
 9. Themethod of claim 6, wherein: the number of NS pulses per cardiac cycleare delivered during an NS ON window of time where the NS ON window oftime lengthens as the cardiac cycle duration increases and decreases asthe cardiac cycle duration decreases; controlling delivery of the userprogrammable NS dose of INS therapy using the sensed cardiac events totime delivering of the programmable number of NS pulses per cardiaccycle includes changing a pulse frequency to distribute the NS pulsesacross the NS ON window of time, wherein the pulse frequency increasesas the NS window of time decreases and the pulse frequency decreases asthe NS window of time increases; and the sensed physiological parameteris indicative of heart rate changes, and adjusting includes increasingthe number of NS pulses per cycle when the sensed physiologicalparameter indicates an increased heart rate.
 10. The method of claim 6,wherein adjusting, based on the sensed physiological parameter, thenumber of NS pulses per cardiac cycle to be delivered during the portionof the cardiac cycles includes implementing a rate smoothing algorithmto slow a response time to a change in the sensed physiologicalparameter.
 11. The method of claim 1, wherein sensing cardiac eventswithin the cardiac cycles includes declaring a cardiac event afterperiod of time without a sensed cardiac event after the previous cardiacevent.
 12. The method of claim 1, further comprising, deriving a currentrate based on a current cardiac cycle or based on an average of heartrates over two or more cardiac cycles.
 13. A system, comprising: aprogramming system with a dose programming interface configured for useby a clinician to program a value for a programmable neural stimulation(NS) dose as a number of NS pulse per cardiac cycle, the programmingsystem with the dose programming interface being configured to display adose meter to provide an indicator of a dose over a period of timeincluding a total charge delivered over the period of time, and theindicator of the dose provided on the displayed dose meter being for acurrent user programmable NS dose, or for a user proposed NS dose, orfor both the current user programmable NS dose and the user proposed NSdose; a cardiac cycle monitor configured to monitor cardiac eventswithin cardiac cycles; a neural stimulator configured to deliver NS tothe autonomic neural target; a memory configured to store theprogrammable NS dose parameter for an intermittent neural stimulation(INS) therapy, the programmable NS dose parameter including the valuefor the number of NS pulses per cardiac cycle; a communication systemconfigured to receive programming instructions for the NS dose parameterincluding the value for the number of NS pulses per cardiac cycle, andstore the value for the number of NS pulses per cardiac cycle in thememory; a controller configured to control the neural stimulator todeliver the INS therapy to the autonomic neural target, wherein thecontroller, the memory, the neural stimulator and the cardiac cyclemonitor are configured to cooperate to implement a process to deliverthe INS therapy, comprising: sensing a cardiac event within a cardiaccycle; and delivering NS bursts of NS pulses, including timing deliveryof the NS bursts using the sensed cardiac events within the cardiaccycles, including delivering the number of NS pulses per cardiac cycleduring a first portion of a cardiac cycle, a remaining portion of thecardiac cycle being without NS pulses.
 14. The system of claim 13,wherein: the memory is configured to store pre-set doses, the pre-setdoses including a normal dose of a first number of pulses per cycle anda higher dose of a second number of pulses per cycle, the second numberbeing greater than the first number; and the communication system isconfigured to receiving instructions to program one of the pre-set dosesto provide the value for the number of NS pulses per cardiac cycle inthe memory.
 15. The system of claim 13, wherein: the memory isconfigured to store pre-set doses, the pre-set doses including a firstnumber of pulses per cycle during an active state and a second number ofpulses per cycle during a resting state; the system further including asensor configured to sense if a patient is in the resting state or theactive state; and the controller configured to select one of the pre-setdoses based on whether the patient is in the resting state or the activestate.
 16. The system of claim 13, wherein the system further includes asensor configured to sense a physiological parameter for use indetermining a heart rate change, the controller configured to determinethe heart rate change based on the sensed physiological parameter andadjust, based on the heart rate change, the number of NS pulses percardiac cycle to be delivered during the portion of the cardiac cycles.17. The system of claim 13, wherein the controller is configured to:deliver the number of NS pulse per cardiac cycle during an NS ON windowof time, and control delivery of the number of NS pulses per cardiaccycle to occur within a refractory period of the cardiac cycle where theNS ON window of time lengthens as the cardiac cycle duration increasesand decreases as the cardiac cycle duration decreases; and change apulse frequency to distribute the NS pulses across the NS ON window oftime, wherein the pulse frequency increases as the NS window of timedecreases and the pulse frequency decreases as the NS window of timeincreases.
 18. A method for programming a neural stimulator to deliverintermittent neural stimulation (INS) to an autonomic neural target of apatient, the INS therapy including neural stimulation (NS) ON timesalternating with NS OFF times, the method comprising: programming aprogrammable NS dose parameter for the INS therapy, includingprogramming a value in units of NS pulses per cardiac cycle for theprogrammable NS dose parameter, the value for the programmable NS doseparameter being programmable by a clinician, and displaying a dose meteron a display to provide an indicator of a dose over a period of timeincluding a total charge delivered over the period of time, and theindicator of the dose provided on the displayed dose meter is for acurrent user programmable NS dose, or for a user proposed NS dose, orfor both the current user programmable NS dose and the user proposed NSdose, the INS therapy including an NS burst of NS pulses during aportion of the cardiac cycle corresponding to one of the NS ON times andno NS pulses during a remaining portion of the cardiac cyclecorresponding to one of the NS OFF times, wherein the number of pulsesin the NS burst is the number of NS pulses per cardiac cycle.
 19. Themethod of claim 18, wherein: programming the value for the programmableNS dose parameter for the INS therapy includes programming a maximumnumber of pulses per cardiac cycle permitted for the INS therapy; andthe neural stimulator is configured to adjust the number of pules in theNS burst in response to a current cardiac rate derived from a sensedphysiological parameter.